When considering treatment, one must remember that the more complex the protocol, the longer the first remission, higher the cost and toxicity. The following is a general overview of canine lymphoma.

Background

Malignant lymphoma (lymphosarcoma) is a lymphoproliferative tumor of solid lymphoid tissues with possible marrow metastasis and a leukemic phase. In dogs, it accounts for 5-7% of all tumors seen and occurs at an incidence rate of 24 cases per 100,000 dogs. It occurs most commonly between 5 and 12 years of age. Boxers, Cocker Spaniels, Fox Terriers, German Shepherds, Scottish Terriers and Golden Retrievers are at an increased risk when compared with other breeds. Etiology for the canine is unknown. In the cat, 90% of the cases are FeLV related and it occurs at an incidence rate of 41.6 cases per 100,000 cats. This accounts for one third of all feline neoplasms and is two and one-half times the rate of lymphoid neoplasia in man. There is a slight male>female predominance in cats.

Clinical Signs

The clinical presentation of canine malignant lymphoma is most commonly that of a multicentric nature with peripheral lymphadenopathy being the most striking feature; however, any organ may be affected. In the cat alimentary involvement is the most common presentation. Other anatomic presentations for both the dog and the cat include anterior mediastinal, cutaneous, and unclassified (e.g., mucocutaneous, CNS, renal) forms. Ocular involvement (anterior uveitis, hypopyon, hemorrhage, infiltrate) is seen in approximately 20-25% of canine cases of malignant lymphoma. Involvement of the spleen, liver, and bone marrow is common in both dogs and cats.

Diagnosis

Once clinical findings compatible with a diagnosis of malignant lymphoma have been found, aspiration and cytology of accessible lesions should be completed. Malignant lymphoma is characterized by the replacement of normal lymph nodes by a uniform population of pleomorphic and bizarre lymphocytes. After a tentative diagnosis of malignant lymphoma has been supported through rapid cytologic methods, confirmation of the diagnosis may be conducted by biopsy. A tissue core may be obtained by Tru-Cut biopsy or, preferably, a node may be excised for final confirmation.

If a dog or cat is to undergo therapy, clinical staging is mandatory. Clinical staging determines the extent of disease in the living animal. Once a baseline of data has been obtained, the clinical oncologist will be able to know which parameters should be monitored in order to reach complete remission. Clinical staging should include radiography of the thorax and abdomen, a complete blood count and platelet count, a bone marrow aspirate and core, an ophthalmic exam, measurement of representative enlarged lymph nodes and a biochemistry panel with special emphasis on calcium and protein levels. Abnormal findings beyond lymphadenopathy are rare, however marrow infiltrate with subsequent release of cells into the peripheral blood is occasionally seen. Hypercalcemia associated with a parathyroid-hormone-like substance is observed in some dogs with malignant lymphoma. This is most often encountered in dogs with anterior mediastinal lymphoma and bone marrow involvement.

Prognostic Factors

Prognostic factors are difficult to confirm due to the variation from study to study. Most treatment reports indicate that hypercalcemia and poor performance status are predictive of short remission and survival times. Animals with advanced clinical stages (World Health Organization Stage IV and V), or at least those with malignant cells in their bone marrows, are also considered to have a poorer prognosis than those animals with less advanced clinical stages (WHO Stage I-III). Some reports suggest that treatment with glucocorticoids prior to therapy with more aggressive chemotherapeutic agents cause a poorer response to therapy than seen in dogs which have not been treated with glucocorticoids, but this finding has not been consistently observed.

Histopathology

Considerable controversy exists regarding the value of histopathologic classification of canine malignant lymphoma in regards to prognostic criteria. The Rappaport classification scheme is of little value because nearly all canine lymph node biopsies are classified as diffuse lymphocytic poorly differentiated, thus preventing subgroups of animals to be studied. The National Cancer Institute-Working Formulation (NCI-WF) allows biopsied tissues to be classified in several categories, but once again, the vast majority of classifications fall within either the diffuse large cell or immunoblastic groups and no consistent differences have been observed in remission or survival times for dogs in these two subgroups. Classification in other categories of the NCI-WF might show predictability, but so few cases of canine malignant lymphoma are classified in those categories that firm recommendations for pet owners based on these criteria is not possible.

Therapy

Treatment for malignant lymphoma must be systemic in nature since it is a multi-system disease. Chemotherapy is most frequently utilized; however, some immunotherapy has been effective. Untreated, dogs affected with malignant lymphoma live an average of only six weeks once a diagnosis has been made. With chemotherapy, dogs can survive for 6-10 months with an excellent quality of life. Dosage of chemotherapeutic agents for the cat is the same as for the dog except when Adriamycin is used. While dogs may receive Adriamycin every 21 days at a dosage of 30 mg/m2, cats appear to be more sensitive to the drug and many of them can only tolerate a dosage of 20 mg/m2 given every 21 days. Anorexia and renal failure have been reported as significant side effects in cats.

Malignant lymphoma is one of the most responsive forms of cancer presented to the practitioner. With appropriate chemotherapy protocols, nearly 90% of animals placed on therapy should reach complete remission. Of those that reach remission, approximately 80-90% will maintain a reasonable (>6 mos) timeframe of excellent quality life. Cost is not inexpensive; however, it is within reasonable financial reach of many clients, thus allowing therapy to be possible.

Although marginally effective, prednisone is inexpensive and often used in combination with other drugs to treat lymphoma. With prednisone therapy, the average pet lives 2 months. One-third of the dogs and cats treated with prednisone will go into complete remission, one-third will go into partial remission, and one-third will not respond at all.

Adriamycin is one of the most effective single agent treatments for lymphoma in dogs. Of the dogs treated with adriamycin, 81% developed a complete and partial remission. The duration of remission is approximately 9 months. Dogs treated with Adriamycin and then switched to COP (cyclophosphamide, Oncovin, prednisone) had a higher second remission rate compared to those started on COP and then switched to Adriamycin.

The COP protocol is effective for inducing a remission in 75% of dogs with lymphoma.

A median duration of remission of 6 months is commonly seen. Approximately twenty percent of the dogs treated with the COP regimen are in remission at 1 year. In one study, 79% of cats with lymphoma treated with COP achieved a complete remission whereas only 29 percent of cats treated for lymphoblastic leukemia achieved a complete remission. Cats with lymphoma treated with COP had a shorter remission time (64% achieved a complete remission, median remission 5 months) but proportionately more long-term, survivors than dogs. Cats with renal lymphoma tend to have recurrence of tumor in the brain, therefore cytosine arabinoside is frequently recommended as an additional therapy.

The addition of adriamycin to the COP regiment resulted in longer remission time (7 months vs 6 months). A complete remission was attained in eighty-four percent of dogs treated with COPA. An additional 7% achieved a partial remission. Twenty-two percent of dogs treated with the COPA protocol were in remission at one year (Table 1).

Table 1. COPA protocol for Dogs+

Drug

Dose

(mg/m2)

1

2

3

4

5

6

7

8

9

10

11

12

13

52

Cytoxan

250 PO

X

X

X

X

Adriamycin*

30 IV

X

X

Vincristine

0.75 IV

X

X

X

X

X

X

Prednisone** 30 PO

>

>

>

>

>

>

>

>

>

+ This protocol can be used in cats if the dosage of adriamycin is reduced to 15-20 mg/m2.
* Adriamycin is given every other treatment during the maintenance phase for a total accumulative dosage for a total accumulative dosage of 250 mg/m2.
** Prednisone is given daily for the first 21 days, then every other day thereafter.

Garrett et al (JVIM 16: 704-709, 2002) compared a maintenance-free chemotherapy protocol based on CHOP to a similar protocol with a maintenance phase for the treatment of canine lymphoma. Fifty-three dogs with multicentric lymphoma were treated with a 6-month modified version of the University of Wisconsin (UW)-Madison chemotherapy protocol. Disease-free interval (DFI) and survival were compared to a historical control group of 55 dogs treated with a similar protocol with a prolonged maintenance phase. Remission rate for the study dogs was 94.2%. The remission and survival between the 2 groups did not differ significantly. Thus, we and others believe the 6-month chemotherapy protocol based on CHOP with no maintenance phase provides is equal to a similar protocol with a prolonged maintenance phase.

WISCONSIN PROTOCOL FOR LYMPHOMA CLIENT INFORMATION SHEET

Chemotherapy is a word that creates an instant emotional response in everyone. Chances are that you, or someone you know, have experienced chemotherapy for the treatment of cancer. The reality of chemotherapy for animals is generally different from that for human cancer patients. Most people are pleasantly surprised at how well their dog or cat feels while undergoing chemotherapy.

The Wisconsin Protocol is a treatment regiment used to fight lymphoma. Most of the drugs are administered by the veterinary health care team by injection (vincristine, doxorubicin, cyclophosphamide, 1-asparagnase) or orally (prednisone, and sometimes cyclophosphamide). If therapy is to be administered by injection, the patient lies quietly on a padded table during administration and rarely needs any form of sedation.

Practically all anticancer drugs have side effects. However, their potential effect against the cancer generally outweighs the possible side effects. Although serious adverse effects can occur with any chemotherapy, there is less than a 5% chance that your dog or cat will be hospitalized with side effects and less than a 1% chance of fatality. Below are listed the possible benefits and side effects of the Wisconsin Protocol. Our goal is to make you as aware of the possible side effects as possible. Please consult your dog or cat's doctor with any questions you may have about chemotherapy.

Whisker or Hair Loss (Alopecia)

When a person loses hair as a result of chemotherapy, it can be devastating. Dog or cats rarely lose their hair, and if they do, they are not bothered by it as much as people are. In most animals, hair does not grow continually throughout their lives like it does in people. Therefore, hair loss in dog or cats is rare except in dogs that need constant hair trims such as Poodles, Schnauzers, and Old English Sheepdogs. Exceptions are certain breeds of dogs, such as poodles, Old English Sheepdogs and other breeds whose hair grows continually. In general, if your dog or cat needs to visit a groomer periodically to be clipped, then your dog or cat may experience some degree of hair loss as a result of chemotherapy. Dog or cats may, however, lose all or most of their whiskers. Please ask your dog or cat's doctor about the possibility of hair loss in your dog or cat.

Reduction in the Number of White Blood Cells (Neutropenia)

There are various types of cells in the blood. The decrease in the number of infection fighting white blood cells is known as neutropenia. Many chemotherapeutic agents impair the bone marrow's ability to produce cells. As a result, neutropenia may occur seven to ten days after chemotherapy. Neutropenia, alone, is not a danger to your dog or cat. However, your dog or cat's ability to fight off infection is impaired by neutropenia. Your dog or cat is given a complete physical, and a blood test called a complete blood count (CBC) is performed prior to each drug treatment. Should your dog or cat have a significant reduction in the number of white blood cells, your veterinarian may wish to perform periodic blood tests, and/or prescribe antibiotics to protect your dog or cat from infection.

Stomach or Intestinal (Gastrointestinal) Discomfort

Many patients experience some form of stomach or intestinal discomfort two to seven days after a chemotherapy treatment. Your veterinarian will prescribe medication to try to prevent or treat the discomfort. Below are listed some steps you can take at home.

Upset stomach (Nausea)

1. If your dog or cat begins to show any signs of upset stomach (drooling, 'smacking' lips) or loss of appetite, administer the medicine your doctor prescribed for nausea.

5. Call your veterinarian if you have concerns, or if the condition persists for more than 24 hours.

Tissue Damage

If Adriamycin®, is accidentally given outside the vein, severe tissue reactions can result. Therefore, drugs like Adriamycin is handled with the utmost care, and is only administered by highly trained professionals. If irritation of the injection site develops in the form of pain or redness, apply ice packs for 15 minutes every three hours. Call your veterinarian if you have concerns, and certainly if the condition persists for more than 24 hours.

Allergic Reactions

Allergic reaction to chemotherapeutic agents is rare, and not a problem you will have to treat at home. Should your dog or cat have an allergic reaction to any drug, it would develop upon administration, and your veterinarian and the hospital staff are trained to treat patients for allergic reaction.

Heart Damage

Adriamycin®, in some rare cases, can irreversibly damage the heart muscle. The dose of Adriamycin® prescribed for your dog or cat is below the dose that usually causes heart disease. Less than 10% of our patients develop heart disease as a result of Adriamycin® chemotherapy. Your veterinarian will discontinue the use of Adriamycin® if heart disease is detected at any time.

Increased Drinking of Water, Urination and Appetite

Prednisone can cause increased drinking of water, urination, panting and enhanced appetite. This is usually mild and self limiting, but in some patients it can be quite marked.

Each Visit

It is important to make an appointment for each chemotherapy administration. At each visit, a doctor or an oncology nurse will admit your dog or cat. We work as a team to minimize the time you and your dog or cat will spend at the hospital. This team approach maximizes quality care. This may mean you might not see the same veterinarian or nurse each time, but the intent is to provide the most comprehensive and compassionate care possible. You will be asked how your dog or cat has been doing since the last visit. This is a good time to express concerns you have about your cat's condition and let us know if you need refills of any medications. Your dog or cat will receive a complete physical examination by a doctor, and blood will be drawn for a complete blood count. Once the blood values have been reviewed, and are determined to be within normal limits, your dog or cat will receive a treatment. This entire process takes two to three hours. You may wait in the lobby during this time, or you may leave your dog or cat in our care and return later in the day. Stop by the Business Office at the completion of each visit to keep your account current (Table 2).

Table 2. Wisconsin Protocol--Short Lymphoma Protocol Treatment

DATE

DOSE

Week 1

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Asparaginase, 400 U/kg SQ

_________

_________

Prednisone, 2 mg/kg PO s.i.d.

_________

_________

Week 2

Cytoxan, 250 mg/m2 IV

_________

_________

Prednisone, 1.5 mg/kg PO s.i.d.

_________

_________

Week 3

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Prednisone, 1.0 mg/kg PO s.i.d.

_________

_________

Week 4

Adriamycin, 30 mg/m2 IV

_________

_________

Prednisone, 0.5 mg/kg PO s.i.d.

_________

_________

Week 6

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Week 7

Cytoxan, 250 mg/m2 IV

_________

_________

Week 8

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Week 9

Adriamycin, 30 mg/m2IV

_________

_________

Week 11

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Week 13

Cytoxan, 250 mg/m2 IV

_________

_________

Week 15

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Week 17

Adriamycin, 30 mg/m2IV

_________

_________

Week 19

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Week 21

Cytoxan, 250 mg/m2 IV

_________

_________

Week 23

Vincristine, 0.5-0.7 mg/m2 IV

_________

_________

Week 25

Adriamycin, 30 mg/m2 IV

_________

_________

Another protocol involves administering adriamycin at 30 mg/m2 body surface area q3 weeks for 5 treatments as long as the dog stays in remission. One day after the first adriamycin therapy, l-asparaginase is administered IM weekly for 3 treatments (10,000 Units/m2). When the patient comes out of remission, then COP therapy is started as mentioned above. The duration of remission 1 plus remission 2 is similar the COPA protocol noted above with less toxicity and less cost to the client.

Rassnick and colleagues (J Vet Intern Med 16[5]:576-580 2002) evaluated the efficacy and toxicity of the MOPP chemotherapy protocol (mechlorethamine, vincristine, procarbazine, and prednisone) as a rescue regimen in dogs with lymphoma. In that study, one hundred seventeen dogs that had resistance to previously administered chemotherapy were evaluated. Thirty-one percent had a complete response (CR) to MOPP for a median of 63 days. Five dogs developed septicemia, and 2 died as a result. MOPP was an effective treatment for dogs with resistant lymphoma but caution should be employed to monitor for septicemia.

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